title: CCL3-CCR5 axis regulates intratumoral accumulation of leukocytes and fibroblasts and promotes angiogenesis in murine lung metastasis process.
abstract: Metastasis proceeds through interaction between cancer cells and resident cells such as leukocytes and fibroblasts. An i.v. injection of a mouse renal cell carcinoma, Renca, into wild-type mice resulted in multiple metastasis foci in lungs and was associated with intratumoral accumulation of macrophages, granulocytes, and fibroblasts. A chemokine, CCL3, was detected in infiltrating cells and, to a lesser degree, tumor cells, together with an infiltration of leukocytes expressing CCR5, a specific receptor for CCL3. A deficiency of the CCL3 or CCR5 gene markedly reduced the number of metastasis foci in the lung, and the analysis using bone marrow chimeric mice revealed that both bone marrow- and non-bone marrow-derived cells contributed to metastasis formation. CCL3- and CCR5-deficient mice exhibited a reduction in intratumoral accumulation of macrophages, granulocytes, and fibroblasts. Moreover, intratumoral neovascularization, an indispensable process for metastasis, was attenuated in these gene-deficient mice. Intrapulmonary expression of matrix metalloproteinase (MMP)-9 and hepatocyte growth factor (HGF) was enhanced in wild-type mice, and the increases were markedly diminished in CCL3- and CCR5-deficient mice. Furthermore, MMP-9 protein was detected in macrophages and granulocytes, the cells that also express CCR5 and in vitro stimulation by CCL3-induced macrophages to express MMP-9. Intratumoral fibroblasts expressed CCR5 and HGF protein. In vitro CCL3 stimulated fibroblasts to express HGF. Collectively, the CCL3-CCR5 axis appears to regulate intratumoral trafficking of leukocytes and fibroblasts, as well as MMP-9 and HGF expression, and as a consequence to accelerate neovascularization and subsequent metastasis formation.
authors.affiliation: Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wu
authors.forename: Ying-Yi
authors.initials: YY
authors.lastname: Li
authors.forename: Kouji
authors.initials: K
authors.lastname: Matsushima
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Baba
authors.forename: Naofumi
authors.initials: N
authors.lastname: Mukaida
mesh_terms: D000276:Adjuvants, Immunologic / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000276:immunology / Q000473:pathology / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D054405:Chemokine CCL3 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D007962:Leukocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000098:blood supply* / Q000276:immunology / Q000473:pathology / Q000556:secondary*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D054389:Receptors, CCR1 / Q000172:deficiency / Q000235:genetics; D019713:Receptors, CCR5 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D000276:Adjuvants, Immunologic; C496534:Ccl3 protein, mouse; C515301:Ccr1 protein, mouse; D054405:Chemokine CCL3; D054389:Receptors, CCR1; D019713:Receptors, CCR5